Reaction of 1,2-trans-glycosyl acetates with thiourea: A new entry to 1-thiosugars

Article abstract of DOI:10.1016/j.tetlet.2003.08.120

The reaction of 1,2-trans-glycosyl acetates with thiourea under boron trifluoride etherate catalysis affording acetylated S-glycosyl isothiourea derivatives is described. The isothiourea derivatives obtained can be readily transformed into the desired 1-thiosugar derivative by reaction with triethylamine and subsequent alkylation or acylation of the in situ formed 1-thioaldose.

Full text of DOI:10.1016/j.tetlet.2003.08.120

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7961–7964
Reaction of 1,2-trans-glycosyl acetates with thiourea:
a new entry to 1-thiosugars
Farid M. Ibatullin,a,* Konstantin A. Shabalin,a Janne V. Ja¨nisb and Alexander G. Shavvac
aMolecular and Radiation Biophysics Division, Petersburg Nuclear Physics Institute, Gatchina 188300, Russia
bDepartment of Chemistry, University of Joensuu, Joensuu, Finland
cChemical Department of Petersburg State University, St.-Petersburg, Russia
Received 14 July 2003; revised 20 August 2003; accepted 29 August 2003
Abstract—The reaction of 1,2-trans-glycosyl acetates with thiourea under boron trifluoride etherate catalysis affording acetylated
S-glycosyl isothiourea derivatives is described. The isothiourea derivatives obtained can be readily transformed into the desired
1-thiosugar derivative by reaction with triethylamine and subsequent alkylation or acylation of the in situ formed 1-thioaldose.
© 2003 Elsevier Ltd. All rights reserved.
1-Thiosugars have attracted considerable attention over
the last decades. Due to their close structural similarity
to the natural O-glycosides they have been widely used
in biochemical1 and structural2 investigations of gly-
cosidases. Owing to the stability of a thioglycosidic
bond to enzymatic cleavage, thioglycosides have been
considered as very promising candidates for the prepa-
ration of carbohydrate-based therapeutics.3 Thiogly-
cosides have found wide applications in carbohydrate
chemistry as very convenient glycosyl donors. The cur-
rent progress in the synthesis of complex oligosaccha-
rides has been greatly related to the development of
new versatile glycosylation methods utilizing thiogly-
cosides as glycosyl donors.4
One of the most convenient and simple approaches for
the stereoselective synthesis of 1,2-trans-thioglycosides
is based upon utilization of S-glycosyl isothiourea
derivatives as starting compounds.7 Recently, we have
shown that isothiourea derivatives of sugars can also be
successfully
applied
for
the
synthesis
of
thiodisaccharides8 and thiooligosaccharides.9
Up to now, the only method for the preparation of
S-glycosyl isothiourea derivatives is the reaction of
thiourea with glycosyl halides,7 that are generally pre-
pared from sugar peracetates.
However, sugar peracetates can also be used as very
convenient glycosyl-donors, that have been widely uti-
lized for glycosylation of various compounds,10 includ-
ing thiols5 and thioacetic acid.11 Nevertheless, no
attempt has been made to investigate such reactions
with thiourea, which might be a convenient approach
to S-glycosyl isothiourea derivatives, and consequently
to thioglycosides, avoiding the use of mercaptans and
the halogenose preparation step.
The Lewis acid catalyzed reaction of per-O-acetylated
sugars with alkyl or aryl thiols5 is one of the most often
employed approaches for the synthesis of 1-thiogly-
cosides. The method allows synthesizing target com-
pounds in one step directly from readily available
peracetylated sugars, although it often suffers from a
number of drawbacks, including the necessity of work-
ing with malodorous and toxic mercaptans. This
method often leads to the formation of anomerized
products.
Therefore, in the course of our current research12 and
interest in thioglycoside synthesis, we decided to investi-
gate the reactivity of per-O-acetylated sugars with
thiourea.
Alternatively, the conversion can be performed using
alkyl- or arylthiotrimethylsilanes,6 although they are
less available than thiols and, therefore, require special
preparation.
Thiourea readily reacts with various electrophiles,
including carbenium ions, affording S-alkyl isothiouro-
nium salts. So, reactions of thiourea with alkyl alco-
hols,13 oxetanes,14 or with benzoquinones15 under
strongly acidic conditions seem to proceed through a
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.120

7962
F. M. Ibatullin et al. / Tetrahedron Letters 44 (2003) 7961–7964
The strong 1,2-trans-stereoselectivity of the reaction
may be explained by a BF3 induced formation of the
1,2-acyloxonium ion as the reaction intermediate, which
reacts with nucleophiles in only one possible way, lead-
ing exclusively to 1,2-trans substitution products
(Scheme 1). The initially formed isothiourea derivatives
do not undergo anomerization, unlike alkyl or aryl
thioglycosides, which can often be obtained only in the
anomerized form, even under mild reaction conditions.
formation of carbocation intermediate. Very recently a
similar mechanism was postulated for the reaction of
di- and trimethoxybenzyl alcohols with thiourea in
acidic media, leading to the corresponding isothiourea
derivatives.16 It is known that most Lewis acid cata-
lyzed reactions of 1,2-trans-glycosyl esters proceed
through the formation of a 1,2-acyloxonium cation, as
the key intermediate.17 Therefore, we assumed that in
the presence of Lewis acids, sugar peracetates would
also be able to react with thiourea, due to the strong
electrophilic character of the 1,2-acyloxonium ion.
The isothiourea intermediates obtained without isola-
tion can be directly converted into thioglycosides by
alkylation under basic conditions. This was performed
according to a recently described literature method
using the triethylamine promoted reaction in
acetonitrile.8
Indeed, treatment of 1,2-trans-glycosyl acetates with
thiourea in the presence of boron trifluoride etherate in
acetonitrile at room temperature causes a slow disap-
pearance of the staring sugar derivatives leading,
according to TLC analysis, to formation of a more
polar compound. At this temperature the conversion
requires more than 48 hours for completion. At reflux,
the reaction proceeds much faster and is generally over
in 20 min with the full disappearance of the starting
peracetates.
Typical procedures are described as follows. To a solu-
tion of peracetylated mono- or disaccharide (10 mmol)
in anhydrous acetonitrile (20 mL), thiourea (11.0
mmol) and BF3–etherate (21.0 mmol) were added. The
resulting mixture was refluxed until the full disappear-
ance of the starting material, according to TLC, had
occurred (20 min).20 After cooling to room tempera-
ture, triethylamine (31 mmol) and alkyl halide (11
mmol) were added with stirring and the reaction mix-
ture was kept at ambient temperature until the conver-
sion was completed. The solvent was evaporated and
the resulting syrup was diluted with toluene (30 mL)
and washed with water. After drying (MgSO4) and
evaporation the residue was crystallized from an appro-
priate alcohol to give a pure product (Table 1).
In several cases the resulting substances were isolated as
solids by crystallization from an appropriate alcohol
and characterized by mass and NMR spectrometry.18
Electrospray ionization mass spectra of the resulting
solids showed intensive signals of the ions correspond-
ing to the adduct cations [M+H]+, [M+Na]+, [M+K]+
and [2M+H]+ as well as the signals of the fragment
ions, including [M+H−76], that corresponds to the loss
of thiourea.
The interglycosidic bonds of oligosaccharides are stable
under the described reaction conditions. Therefore, the
method can also be successfully applied for the intro-
duction of a thioglycosidic bond into oligosaccharides.
This has been confirmed by syntheses of several thiogly-
cosides of maltose and cellobiose.
1H NMR spectra, in addition to all proton signals of
the acetylated sugar moiety, contained characteristic
signals at 9–9.5 ppm corresponding to four amide
protons, belonging to the isothiouronium fragment of
the molecule. 13C NMR spectra contained a signal at
171.5–171.9, corresponding to the isothiouronium car-
bon. All NMR spectra have close similarity to those
measured for S-glycosyl isothiouronium bromides, pre-
pared using the common procedure.19
Due to the anhydrous reaction conditions, the proce-
dure may also be used for the conversion of sugar
peracetates into glycosyl thioesters according to a
recently described approach.8 Using appropriate acti-
vated sugar derivatives for the coupling reaction, the
procedure can be utilized for the synthesis of the corre-
sponding thio-oligosaccharides, that has been shown to
be successful for the syntheses of several thiodisaccha-
rides, including acylated methyl glycoside of 4-
The substances obtained have shown the chemical
behaviour typical for S-glycosyl isothiouronium
halides, including a conversion into the corresponding
acetylated thioglycoses in basic media and subsequent
transformation into thioglycosides using known proce-
dures. These observations allowed us to conclude that
the substances obtained are S-glycosyl isothiourea
derivatives.
thiogalactobiose (b-
D
-Galp-(1“4)-a-
D
-Galp-OMe) and
octa-O-acetyl-4-thiogentiobiose (b-
D
-Glcp-(1“6)-a-
D-
Glcp).
Scheme 1. Proposed mechanism for boron trifluoride etherate catalyzed reaction of sugar acetates with thiourea.

F. M. Ibatullin et al. / Tetrahedron Letters 44 (2003) 7961–7964
7963
Table 1. Synthesis of 1,2-trans-thioglycosides
Conclusion
3. For reviews, see: (a) Witczak, Z. J. Curr. Med. Chem.
1999, 6, 165–178 and references cited therein; (b)
Tolkach, A. M.; Polonik, S. G.; Stekhova, S. B.;
Prokof’eva, N. G.; Uvarova, N. I. Pharm. Chem. J.
(Engl. Transl.) 1989, 23, 1013–1016; (c) Comber, R. N.;
Friedrich, J. D.; Dunshee, D. A.; Petty, S. L.; Secrist, J.
A. Carbohydr. Res. 1994, 262, 245–255; (d) Kiefel, M. J.;
Beisner, B.; Bennett, S.; Holmes, I. D.; von Itzstein, M. J.
Med. Chem. 1996, 39, 1314–1320; (e) Eisele, T.; Toepfer,
A.; Kretzschmar, G.; Schmidt, R. R. Tetrahedron Lett.
1996, 37, 1389–1392.
The reactions described here of 1,2-trans-glycosyl
acetates with thiourea represent a novel simple route to
1,2-trans-glycosyl isothiourea derivatives. The reactions
provide a very convenient tool for the synthesis of
various 1-thiosugar derivatives, including thiogly-
cosides, thiooligosaccharides and glycosyl thioesters.
4. For reviews, see: (a) Toshima, K.; Tatsuta, K. Chem.
Rev. 1993, 93, 1503–1531, and references cited therein; (b)
Fukase, K.; Hasuoka, A.; Kinoshita, I.; Aoki, Y.;
Kusumoto, S. Tetrahedron 1995, 51, 4923–4932; (c) Nor-
berg, T. In Modern Methods in Carbohydrate Synthesis;
Khan, S. H.; O’Neill, R. A., Eds.; Frontiers in Natural
Product Research Series, Vol 1. Harwood Academic Pub-
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Carbohydr. Chem. Biochem. 1997, 52, 179–205 and refer-
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Methods Carbohydr. Chem. 1980, 8, 251–253; (b)
Lemieux, R. U. Can. J. Chem. 1951, 29, 1070–1091; (c)
Ferrier, R. J; Furneaux, R. H. Carbohydr. Res. 1976, 52,
63–68; (d) Dasgupta, F.; Garegg, P. J. Acta Chem. Scand.
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F. M. Ibatullin et al. / Tetrahedron Letters 44 (2003) 7961–7964
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75.6, 72.3, 71.5 (C-5, C-3, C-2, C-4), 66.5 (C-6), 25.63,
25.6, 25.5, 25.4 (4×CH3-Ac). HRMS (m/z): 407.1113
(407.1124 calcd for C15H22N2O9S [M+H]+).
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(d, 1H, J1,2=7.8 Hz, H-1), 5.16 (dd, 1H, J3,4=7.8 Hz,
H-3), 5.03 (dd, 1H, J2,3=7.8 Hz, H-2), 4.98 (td, 1H,
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12.1 Hz, H-5a), 3.68 (dd, 1H, H-5b), 2.06, 2.03, 2.01 (3s,
3×3H, 3×Ac). 13C NMR (DMSO-d6): l 174.6, 174.4,
174.3 (3×CO-Ac), 171.9 (SC(NH2)2), 85.88 (C-1), 75.1,
73.4, 72.3 (C-3, C-2, C-4), 69.5 (C-5), 25.6, 25.5, 25.4
(3×CH3-Ac). HRMS (m/z): 335.0900 (335.0913 calcd for
C12H19N2O7S [M+H]+).
2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-(1“4)-2,3,6-
8. Ibatullin, F. M.; Selivanov, S. I.; Shavva, A. G. Synthesis
tri-O-acetyl-b-D-glucopyranosyl isothiourea derivative.
1H NMR (DMSO-d6): l 9.20, 8.96 (2s, 2×2H, 2×NH2),
5.58 (d, 1H, J1,2=10.1 Hz, H-1), 5.28 (dd, 1H, J3%,4%=9.6
Hz, H-3%), 5.18 (dd, 1H, J3,4=9.1 Hz, H-3), 4.98 (dd, 1H,
2001, 419–422.
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J
4,5=9.8 Hz, H-4%), 4.88 (dd, 1H, J2,3=9.5 Hz, H-2), 4.82
(d, 1H, J1%,2%=8.0 Hz, H-1%), 4.65 (dd, 1H, J2%,3%=9.6 Hz,
H-2%), 4.39 (dd, 1H, J6a,6b=12.0 Hz, H-6a), 4.24 (dd, 1H,
J
6%a,6%b=12.5 Hz, 6%a), 4.08 (dd, 1H, H-6b), 4.02 (m, 1H,
5%,6%a=4.2 Hz, J5%,6%b=2.2 Hz, H-5%), 3.99 (m, 1H, H-5),
J
3.94 (dd, 1H, J4,5=8.7 Hz, H-4), 9.93 (dd, 1H, H-6%b),
2.08, 2.04, 2.00, 1.98, 1.97, 1.96, 1.91(7s, 7×3H, 7×Ac).
13C NMR (DMSO-d6): l 175.4, 175.2, 174.8, 174.6, 174.5,
174.4, 174.2 (7×CO-Ac), 171.6 (SC(NH2)2), 104.78 (C-1%),
84.78 (C-1), 81.7, 80.7, 77.6, 77.3, 76.4, 75.7, 74.1, 72.9,
(C-4, C-5, C-3%, C-2, C-5%, C-2%, C-3, C-4%), 67.0, 66.7
(C-6%, C-6), 25.7, 25.6, 25.5, 25.4, 25.36, 25.3, 25.25
(7×CH3-Ac). HRMS (m/z): 695.2025 (695.1969 calcd for
C27H39N2O17S [M+H]+).
13. Kofod, H. Org. Synth. Coll. Vol. 4 1963, 491–492.
14. Rondestvedt, C. S. J. Org. Chem. 1961, 26, 3024–3026.
15. Daneke, J.; Jahnke, U.; Pankow, B.; Wanzlick, H.-W.
Tetrahedron Lett. 1970, 11, 1271–1272.
19. See for example data for 2,3,4,6-tetra-O-acetyl-b-D-
16. Vetter, S. Synth. Commun. 1998, 28, 3219–3223.
17. For reviews see: (a) Lemieux, R. U. Adv. Carbohydr.
Chem. 1954, 9, 1–57; (b) Paulsen, H. Adv. Carbohydr.
Chem. 1971, 26, 127–195.
galactopyranosyl isothiouronium bromide: 1H NMR
(DMSO-d6): l 9.39, 9.17 (2s, 2×2H, 2×NH2), 5.85 (d, 1H,
J
1,2=10.1 Hz, H-1), 5.37 (dd, 1H, J4,5=1.1 Hz, H-4),
5.21 (dd, 1H, J3,4=3.4 Hz, H-3), 5.09 (dd, 1H, J2,3=9.9
Hz, H-2), 4.51 (td, 1H, J5,6a=6.4 Hz, J5,6b=5.9 Hz, H-5),
4.08 (dd, 1H, J6a,6b=11.5 Hz, H-6a), 4.05 (dd, 1H, H-6b),
2.12, 2.07, 2.00, 1.93 (4s, 4×3H, 4×Ac). 13C NMR
(DMSO-d6): l 169.94, 169.92, 169.7, 169.4 (4×CO-Ac),
166.5 (SC(NH2)2, 80.06 (C-1), 74.4, 70.5, 67.2, 66.4 (C-5,
C-3, C-2, C-4), 61.3 (C-6), 20.6, 20.5, 20.46, 20.4 (4×CH3-
Ac).
18. Selected data21 for several isolated S-glycosyl isothiourea
derivatives:
2,3,4,6-Tetra-O-acetyl-b-
D
-glucopyranosyl
isothiourea
derivative. 1H NMR (DMSO-d6): l 9.17, 9.01 (2s, each
2H, 2×NH2), 5.62 (d, 1H, J1,2=9.9 Hz, H-1), 5.31 (dd,
1H, J3,4=9.6 Hz, H-3), 5.11 (dd, 1H, J2,3=9.6 Hz, H-2),
5.10 (dd, 1H, J4,5=9.6 Hz, H-4), 4.20 (dd, 1H, J6a,6b
=
12.1 Hz, J5,6a=4.9 Hz, H-6a), 4.14 (m, 1H, H-5), 4.09
(dd, 1H, H-6b), 2.05, 2.02, 1.99, 1.97 (each s, 4×3H,
4×Ac). 13C NMR (DMSO-d6): l 175.2, 174.7, 174.5,
174.42 (4×CO-Ac), 171.5 (SC(NH2)2), 85.05 (C-1), 80.6,
77.6, 73.9, 72.6 (C-5, C-3, C-2, C-4), 66.8 (C-6), 25.6,
25.5, 25.4, 25.3 (CH3-Ac). HRMS (m/z): 407.1096
(407.1124 calcd for C15H22N2O9S [M+H]+).
20. The S-glycosyl isothiourea derivatives can be isolated on
this step by an addition of pyridine (21.0 mmol) and
concentration of resulting mixture under the reduced
pressure. A dilution of the obtained syrups with 2-
propanol (5–10 mL) resulted in precipitation of pyridine–
boron trifluoride complex, which was removed by
filtration. The resulting filtrates were diluted with 2-
propanol (20–30 mL) to give crystalline products, which
were recrystallised from 2-propanol or from ethanol to
give the target products.18
2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl isothiourea
1
derivative. H NMR (DMSO-d6): l 9.27, 9.04 (2s, 2×2H,
2×NH2), 5.61 (d, 1H, J1,2=9.9 Hz, H-1), 5.39 (dd, 1H,
J
4,5=1.0 Hz, H-4), 5.24 (dd, 1H, J3,4=3.4 Hz, H-3), 5.12
(dd, 1H, J2,3=10.0 Hz, H-2), 4.39 (td, 1H, J5,6a=7.0 Hz,
5,6b=5.4 Hz, H-5), 4.11 (dd, 1H, J6a,6b=11.5 Hz, H-6a),
4.07 (dd, 1H, H-6b), 2.14, 2.08, 2.01, 1.95 (4s, 4×3H,
21. The NMR data is presented using the convention fol-
lowed in Carbohydrate Research (see Instructions to
Authors).
J